Cancer cells survive with survivin

Survivin regulation

One of the mechanisms of survivin regulation is at the transcriptional level (Fig. 3). Survivin promoter activity is regulated through the β‐catenin activated T‐cell factor (TCF) transcription factor.^{( 16 )} The expression of survivin is also Sp1‐dependent, with transcriptional activity requiring two critical Sp1 sites.^{( 17 )} Another report indicates that Sp1‐mediated survivin expression is further subject to a p53‐mediated transcriptional repression.^{( 18 )} Other transcriptional regulation is mediated by Stat3.^{( 19 )} Stat3 inhibitors down‐regulate survivin in human breast and ovarian cancer cells.^{( 20 )} However, we have reported that the Sp1 transcription factor, rather than Stat3, dominantly regulated promoter activity of survivin in esophageal cancer and gastric cancer; thus the regulation mode appears to be highly cell‐type specific.^{( 21 )} Hypoxia‐inducible factor‐1 alpha (HIF‐1α) is another transcription factor involved in survivin regulation. Epidermal growth factor (EGF)–stimulated survivin up‐regulation was mediated by HIF‐1α in breast cancer cell lines.^{( 22 )}

Survivin is a relatively short‐lived protein (t_1/2 at 30 min), regulated by proteasome degradation after polyubiquitination.^{( 23 )} In addition of transcriptional level, the survivin protein becomes stable by phosphorylation of Thr34 by cdc2, which slows down clearance of survivin through the proteasome degradation.^{( 24 )} Flavopiridol down‐regulates survivin through inhibition of phosphorylation of Thr34.^{( 25 )} Cyclin‐dependent kinase inhibitor, NU6140, and paclitaxel combination also cause down‐regulation of survivin through the inhibition of phosphorylation of Thr34 and enhanced caspase‐dependent apoptosis in the HeLa cervical carcinoma cell line and an ovarian cell line.^{( 26 )} Heat shock protein 90 (Hsp90), well known for its chaperone activity, has also been reported to regulate survivin. The disruption of survivin–Hsp90 interaction has been shown to result in the proteasome degradation of survivin, leading to mitotic defects and apoptosis.^{( 27 )}

The Akt signaling pathway is also involved in survivin expression. Geranylgeranyltransferase I inhibitors (GGTIs) induce apoptosis in ovarian cancer cells by inhibition of the PI3K/AKT and survivin pathways.^{( 28 )} A new class of anticancer drug, Trichostatin A (TCA), inhibitor of mammalian histone deacetylase (HDAC), also transiently induces survivin expression via activation of the EGFR/PI3K/Akt cell survival pathway.^{( 29 )} Treatment of small cell lung cancer cells with cisplatin leads to up‐regulation of survivin through the Akt survival pathway.^{( 30 )}

Up‐regulation of survivin in human malignancies

Survivin is expressed in embryonic and fetal tissues, but is almost undetectable in adult tissues.^{( 1} , ^{3 )} However, overexpression of survivin has been reported in almost all human malignancies including lung cancer, breast cancer; stomach, esophagus, liver, and ovary cancers; and brain and hematological cancers.^{( 1} , ^{31 )} Based on detection of protein by immunohistochemistry and mRNA by polymerase chain reaction techniques, overexpression of survivin has been reported in various human malignancies (Table 1 ^{( 32} , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ^{45 )}). Similar to its expression, survivin promoter activity is largely silent in normal cell types, but is increased in tumor cell lines.^{( 46 )}

The specific up‐regulation of survivin in cancer cells is further supported by the immunological responses detected against it. Survivin‐specific CD8⁺ T‐cell‐mediated and CD4⁺ cell‐mediated immune response have been identified in the peripheral blood of colorectal cancer patients.^{( 47 )} Cytotoxic T‐lymphocyte response to survivin has also been detected in breast, melanoma, and chronic lymphatic leukemia patients.^{( 48 )} Induction of survivin‐specific immune response has been confirmed in vitro.^{( 49 )}

Cancer cells thus seem to utilize the cytoprotective character of survivin to ensure its continual progression. During colorectal carcinogenesis, the expression of survivin was found to increase from adenoma with low‐grade dysplasia (2.3%) to high‐grade dysplasia (52.4%) to carcinoma in adenoma (63.3%).^{( 50 )} Similar results has been found in the tumorigenesis of pancreatic ductal adenocarcinoma. While no expression has been found in normal pancreatic ducts, survivin expression steadily increased from low‐grade pancreatic intraepithelial neoplasia to high‐grade lesions and to the highest in pancreatic ductal adenocarcinoma tissues.^{( 51 )} A study on ovarian cancer has also reported that survivin expression increased from benign tumors (21.2%) to borderline tumors (47.8%) to ovarian carcinomas (51.1%).^{( 52 )} Furthermore, most reports have suggested consistencies with a reduced apoptotic index^{( 53 )} indicating a survival advantage in these tumor cells.

Survivin expression has been shown to induce a global transcriptional change in the tumor microenvironment that may promote tumor progression. In addition to the survival of cancer cells, survivin has been implicated in angiogenesis. Molecular targeting of survivin has led to not only inhibition of tumor growth, but also reduction in tumor‐derived blood vessels.^{( 54 )} Survivin has also showed a cytoprotection effect, possibly mediated by PI3K pathways, on endothelial cells, which is mediated by VEGF.^{( 55 )}

Association between survivin expression and prognosis or therapy resistance

Survivin expression in most cancers is associated with patients’ survival or disease recurrence, and resistance to chemotherapy or radiotherapy. A higher survivin expression has been correlated with an unfavorable survival or disease recurrence in colorectal cancer, particularly in stage II disease^{( 35 )} in esophageal cancer,^{( 56 )} hepatocellular carcinoma,^{( 38 )} lung cancer,^{( 43 )} glioma,^{( 53 )} leukemia,^{( 45 )} and other cancer types. Survivin has been further identified as an independent prognosis factor in multivariate analysis in different patient groups. With regard to chemosensitivity, patients with lower survivin expression were more responsive to preoperative chemotherapy with 5‐flourouracil and cisplatin in esophageal cancer.^{( 57 )} Overexpression of survivin was also associated with clinical resistance to a taxol‐based regimen for ovarian carcinomas.^{( 58 )} It is also reported that patients with lower survivin expression in pretreatment biopsies were more responsive to radiotherapies in rectal cancer.^{( 59 )} Taken together, these findings suggest that diminution of the basal survivin expression in tumor cells would increase sensitivity to cancer therapies.

Modulation of survivin by anticancer drugs

The above evidence in clinics indicates that overexpression of survivin in cancer invariably provides a survival advantage in tumor cells. Therefore, lack of survivin or disruption of the survivin function would cause cell death such as apoptosis and mitotic catastrophe in these cells. In fact, many anticancer drugs currently in use in clinics as well as those still undergoing testing are reportedly shown to have inhibitory effects on survivin. (i) Celecoxib and its derivatives have been shown to down‐regulate survivin in a wide range of tumor cells, including glioblastoma; lymphoma; multiple myeloma; and carcinoma of the breast, colon and prostate, inducing apoptosis.^{( 60 )} (ii) COX‐2 inhibitor etodolac and oxaliplatin have been shown to significantly down‐regulate survivin in human colon cancer cells, causing growth inhibition and cell death.^{( 61 )} (iii) Silibilin derivatives, such as Silymarin, which have showed efficacy toward prostate cancer, have also been shown to down‐regulate survivin.^{( 62 )} (iv) Tetra‐O‐methyl nordihydroguaiaretic acid (a small organic compound with antitumor activity) has been shown to selectively target survivin and cdc2, both Sp1‐regulated proteins that control apoptosis and the cell cycle. Reintroduction of survivin inhibited apoptosis.^{( 63 )} (v) Proteasome inhibitor (MG132 or MG115) has been shown to down‐regulate survivin in hepatocellular carcinoma cell lines.^{( 64 )} (vi) Other novel therapeutic approaches using small molecule inhibitors, nucleoside analogs,^{( 65 )} or natural products or components such as betulinic acid^{( 66 )} indole‐3‐carbinol, found in vegetables,^{( 67 )} have demonstrated anticancer effects, and also been shown to down‐regulate survivin after treatment in certain cell lines used in respective studies.

In the meantime, while survivin is down‐regulated by most anticancer drugs, up‐regulations following treatment regimens have been previously reported. Treatment by taxol, adriamycin, or ultraviolet B irradiation in breast cancer MCF‐7 and cervical cancer HeLa cells have resulted in a four‐ to five‐fold increase in survivin expression, possibly by activation of Thr34 phosphorylation as mentioned above.^{( 68 )} Exposure of cells to radiation or photodynamic therapy similarly caused up‐regulation of survivin.^{( 69 )} Cisplatin has also led to up‐regulation of survivin through the Akt survival pathway in small cell lung cancer cells.^{( 30 )} Supposedly these could be responses for tumor cells to survive in resistance to the various toxic stresses.

Therapeutic approaches

Similar to the conserved mechanism in the developmental process, survivin inhibition has been shown to enhance cell death.^{( 3 )} Various approaches have been attempted to down‐regulate or block survivin in cancer cells to inhibit cell survival and at the same time enhance cell death.

Inhibition of survivin by the molecular approach.

• 1

   Molecular antagonist utilizing antisense, siRNA, ribozyme, dominant‐negative mutants have shown satisfactory results. An approach using short hairpin RNA (shRNA) successfully reduced survivin expression, and induced apoptosis and growth inhibition in a lymphoma cell line.^{( 70 )} Ribozyme‐mediated inhibition of survivin induced polyploidy and caspase‐9‐dependent apoptosis in prostate cancer cells.^{( 71 )} We have shown that siRNA against survivin induced drastic induction of mitotic catastrophe in esophageal cancer cells (Fig. 4). A therapeutic approach using survivin responsive conditionally replicating adenovirus displayed tumor cell specificity, induced tumor cell death and inhibition of tumor growth,^{( 72 )} and also sensitized human melanoma cells to gamma irradiation.^{( 73 )} Replication‐deficient adenovirus encoding a survivin mutant caused massive apoptosis in tumor cells but had no effect on proliferation normal cells.^{( 74 )}

Conclusion

Survivin is one of the highly conserved proteins that are indispensable for cell survival in development. Survivin is repressed or down‐regulated in most normal adult tissues; hence its up‐regulation in cancers could make it a highly specific target. The majority of anticancer drugs, although mediated through different regulatory pathways in different types of cancers, lead to down‐regulation of survivin, which causes cell death through apoptosis or mitotic catastrophe. Up‐regulation of survivin by others nevertheless suggests possible mechanisms of compensation to assure cell survival in certain cells. Inhibition of survivin with novel molecular genetic approaches in combination with the use of chemotherapeutic drugs or radiotherapy may improve some of the current regimen. Although survivin is a potential target for therapeutic purposes, the approaches nevertheless should be carefully designed, considering the possibility of hindering its normal functions in limited adult tissues, such as hematopoietic cells. Further investigation is thus necessary to understand the complex cellular circuitry of survivin in cancer as well as in physiological conditions.